biostudies-literatureYang LBasic Research Program of Jiangsu Province11655https://www.ebi.ac.uk/biostudies/studies/S-EPMC12749320biostudies-literatureUnknown16(1)Pulmonary fibrosis (PF) is a progressive lung disease characterized by chronic immune dysregulation and excessive extracellular matrix (ECM) remodeling. Neutrophils, traditionally linked to acute inflammation, are increasingly recognized for their role in fibrosis. In this study, we identified a unique subset of neutrophils undergoing reverse transendothelial migration (rTEM) in the lungs of a silicosis mouse model induced by intratracheal SiO₂ instillation. Using single-cell RNA sequencing (scRNA-seq), spatial transcriptomics (ST), and ECM proteomics, we found that rTEM neutrophils were retained in fibrotic regions via ICAM1-mediated interactions with the ECM. Mechanistically, macrophage-derived cathepsin C (CTSC), accumulating in the ECM, cleaved ICAM1 into its soluble form (sICAM1), whiNature communicationsExtracellular matrix anchored neutrophils drive pulmonary fibrosis in mice.PMC12749320No. BK20253013Xu MYang LHuang JChao JMao RZi SChen HZhu BWang JYu KZhang WRong YSun PZhang XLuo WMa JFang SLiu CfalseExtracellular matrix anchored neutrophils drive pulmonary fibrosis in mice.Pulmonary fibrosis (PF) is a progressive lung disease characterized by chronic immune dysregulation and excessive extracellular matrix (ECM) remodeling. Neutrophils, traditionally linked to acute inflammation, are increasingly recognized for their role in fibrosis. In this study, we identified a unique subset of neutrophils undergoing reverse transendothelial migration (rTEM) in the lungs of a silicosis mouse model induced by intratracheal SiO₂ instillation. Using single-cell RNA sequencing (scRNA-seq), spatial transcriptomics (ST), and ECM proteomics, we found that rTEM neutrophils were retained in fibrotic regions via ICAM1-mediated interactions with the ECM. Mechanistically, macrophage-derived cathepsin C (CTSC), accumulating in the ECM, cleaved ICAM1 into its soluble form (sICAM1), whi2025-01-01T00:00:00Z2025 Nov2026-07-15T11:45:51.487Z2026-07-05T03:08:18.785ZS-EPMC127493204129846610.1038/s41467-025-66633-8